Most human tumors find ways to resist anticancer drug monotherapy. Akt is considered a likely peptide providing such monotherapy drug resistance. Aurora-A, a serine/threonine protein kinase, activates the Akt pathway in a p53-dependent manner, and thus protects cancer cells from chemotherapeutic-induced apoptosis often involved in cancer resistance to anticancer drug monotherapy.
Akt, also called protein kinase B, is a serine/threonine protein kinase that is activated by extracellular stimuli in a phosphatidylinositol 3′-kinase (PI3k)-dependent manner. Akt has emerged as a crucial regulator of a wide range of cellular processes including apoptosis, proliferation, differentiation, and metabolism. Akt is phosphorylated, and therefore activated, by phosphoinositide dependent kinase 1 (PDK1) and the mammalian target of rapamycin complex 2 (mTORC2). Deregulation of the Akt signaling pathway has been documented as a frequent occurrence in a number of human malignancies. Ectopic expression of Akt induces cell survival and malignant transformation, whereas inhibition of Akt activity stimulates apoptosis. Furthermore, over-expression of active Akt often accompanies increased chemoresistance in cancer cells.
Cisplatin [CDDP, cis-Diammine-dicholoroplatinum(II)], an anti-tumor drug known to induce apoptosis of cancer cells by damaging nuclear DNA, is among the most effective agents used in human cancer chemotherapy. CDDP increases p53 content, leading to up-regulation of proteins promoting cell cycle arrest, such as p21, and of pro-apoptotic proteins such as Bax and Fas leading to activations of both the mitochondrial and death-receptor apoptotic pathways, resulting in the activation of the execution caspase-3 and -7.
Taxol is a plant alkaloid anti-tumor drug which acts on microtubule growth during mitosis. Taxol stabilizes the β tubulin subunit of the microtubule, preventing the dissociation of the microtubule preventing cellular transport and further mitosis. Taxol has likewise been shown to induce apoptosis by stopping Bcl-2.
Farnesyltransferase inhibitors (FTI) and geranylgeranyltransferase inhibitors (GGTI) target farnesyltransferase and geranylgeranyltrasferase, respectively, preventing posttranscriptional modification and function of the Ras protein. Conversely, proteasome inhibitors prevent proteasome activity, preventing the degradation of proteins. Recent proteasome inhibitors selectively abrogate proteasome activity by reacting with the hydroxyl group and N-terminal theronine in the proteasome's active site.
Chemoresistance represents a major obstacle for successful cancer therapy. Increased dosage is required for resistant cells; however large dose treatments often lead to severe side effects in multiple organs.
Akt over expression often accompanies increased chemoresistance in cancer cells. Several studies have established mechanisms by which Akt may contribute to CDDP resistance. For instance, Akt attenuates the CDDP-mediated up-regulation of p53. Phosphorylation of MDM2 by Akt inactivates p53 and in turn prevents p53-mediated cell cycle arrest. Akt also protects anti-apoptotic proteins such as XIAP from CDDP-induced down-regulation. In addition, Akt activity promotes cellular resistance to CDDP through the inhibitions of CDDP-induced JNK and p38 activations required for CDDP's anti-tumor activity